Project 1 Abstract According to a National Sleep Foundation study, 31% of men and 21% of women in the US are at high risk of suffering from sleep apnea (SA). There is a cause-and-effect relationship between SA and increased mean arterial pressure (MAP) and increased sympathetic nerve discharge (SND) which persist even during the daytime when apneic episodes are not occurring. Chronic exposure to intermittent hypoxia (CIH) is a widely used animal model of the arterial hypoxemia that occurs during SA. CIH in animals results in an increased MAP and SND as seen in human SA patients. CIH also enhances the hypothalamic-pituitary-adrenal axis response to stress. The overall hypothesis of this project is that repetitive activation of the arterial chemoreceptors during CIH increases the discharge of and the responsiveness of catecholaminergic and glutamatergic neurons in the nucleus of the solitary tract (NTS) and this provides a sympatho-excitatory drive that underlies the CIH-induced persistent increase in MAP and SND. Three specific aims are proposed to further test this hypothesis. Specific Aim 1 will test the hypothesis that during 7 and 28 days exposure to CIH and CIHHC, arterial chemoreceptor afferents stimulate NTS A2 neurons which activate the HPA axis and induce release of CORT. CORT then enhances glutamatergic transmission to NTS which contributes to the CIH-induced sustained increase in MAP and SND. Specific Aim 2 will test the hypothesis that following 7 & 28 days CIH and CIHHC, descending CRF inputs from PVN provide an excitatory drive to catecholaminergic and glutamatergic NTS neurons that contributes to the sustained increase in MAP and SND. Specific Aim 3 will test the hypothesis that the resistance of NTS neurons to ischemic injury is reduced following 7 & 28 days CIH and CIHHC due to changes in KATP currents. The results of these studies will provide a comprehensive analysis from the system to the cellular level of neuronal and humoral adaptations to CIH will provide new insights into the mechanisms whereby CIH leads to elevated MAP and SND.